Low-dose CsA Research Articles

Graft Function, Cardiovascular Risk Factors, and Sex Hormones in Renal Transplant Recipients on an Immunosuppressive Regimen of Everolimus, Reduced Dose of Cyclosporine, and Basiliximab

A prospective, randomized trial evaluated the combination of everolimus of 1.5 or 3 mg/d with steroids, basiliximab, and low-dose cyclosporine (CsA) adjusted by C 2 monitoring in 256 renal transplant recipients. CsA C 2 target levels, initially set at 600 ng/mL, were tapered over time posttransplant. The median serum creatinine concentrations were 130 μmol/L in both sirolimus groups (1.5 and 3 mg/d) at 6 months. Biopsy-proven acute rejection (BPAR) occurred in 13.7% and 15.1% of patients in the 1.5 and 3 mg/d groups, respectively. The incidence of BPAR was significantly higher among patients with everolimus trough levels < 3 ng/mL. Posttransplant diabetes mellitus occurred rarely, and blood pressure control appeared favorable; however, serum cholesterol levels were increased by ∼50%, and serum triglycerides by ∼100%. Serum testosterone concentrations increased after renal transplantation in both everolimus groups. Concentration-controlled everolimus therapy combined with low-dose CsA provides effective protection against rejection with good renal function and safety profiles.

A Randomized Trial of Steroid Avoidance in Renal Transplant Patients Treated with Everolimus and Cyclosporine

In this randomized trial renal transplant recipients were treated with basiliximab, everolimus 3 mg/day, low-dose CsA. At transplantation, patients were randomized to stop steroids at the seventh day (group A) or to continue oral steroids in low doses (group B). Of the 113 patients enrolled, 65 were randomized to group A and 68 to group B. All patients were followed for 2 years. During the study 28 (43%) group A patients required reintroduced corticosteroids. One patient died, in group B. The Graft survival rate was 97% in group A and 90% in group B. There were more biopsy-proven rejections in group A (32% vs 16%; P = .044). The mean creatinine clearance was 54 ± 21 mL/min in group A vs 56 ± 22 mL/min in group B. Mean levels of serum cholesterol tended to be lower in group A, but the difference was of borderline significance (191 ± 91 vs 251 ± 188 mg/dL; P = .07). Vascular thrombosis (0 vs 5) and pneumonia requiring hospitalization (2 vs 7) tended to be more frequent in group B. Only three cases of CMV infection (1 vs 2) occurred. An immunosuppressive therapy with everolimus and low-dose CsA allows one to obtain excellent renal graft survival and stable graft function at 2 years. Early interruption of steroids in patients treated with this regimen may increase the risk of acute rejection, but neither affects graft survival nor graft function, while possibly reducing the risk of hyperlipemia and vascular thrombosis. About 60% of patients given everolimus and low-dose CsA can definitively stop steroids after 1 week.

Corticosteroid Avoidance Ameliorates Lymphocele Formation and Wound Healing Complications Associated With Sirolimus Therapy

Introduction Sirolimus (RAPA) and corticosteroids (CS) both inhibit wound healing. To evaluate the possibility that RAPA and CS have additive effects on wound healing, we evaluated the effects of corticosteroid avoidance (CSAV) on wound healing complications in patients treated with RAPA. Methods One hundred nine patients treated with a CSAV regimen (no pretransplantation or posttransplantation CS) were compared with a historical control group (n = 72) that received cyclosporine (CsA), mycophenolate mofetil (MMF), and CS. The CSAV group received low-dose CsA, MMF, RAPA, and thymoglobulin induction. Complications were classified as follows: wound healing complications (WHC) or infectious wound complications (IWC). WHC included lymphocele, hernia, dehiscence, diastasis, and skin edge separation. IWC included wound abscess and empiric antibiotic therapy for wound erythema. Results The CSAV group was largely CS-free: 11% of patients received CS for rejection, 12% of patients received CS for recurrent disease, and 85% of patients are currently off CS. The CSAV group had a significantly lower incidence of WHC (13.7% vs 28%; P = .03) and lymphoceles (5.5% vs 16%; P = .02) than the control group. There was no difference in the incidence of IWC between the 2 groups. Patients who received CSAV were 18% less likely ( P = .57) to develop any type of complication, 41% less likely ( P = .20) to develop a WHC, and 71% less likely ( P = .018) to develop a lymphocele. Conclusions CSAV in a RAPA-based regimen results in a marked reduction in WHC and lymphoceles. Therefore, CSAV provides a promising approach for addressing WHC associated with RAPA therapy.

Twelve months results of Enteric-Coated Mycophenolate Sodium (EC-MPS) in de novo heart transplant patients showed excellent efficacy and safety

Enteric-coated mycophenolate sodium (EC-MPS, myfortic®) is a novel formulation designed to release MPA in the small intestine, and therefore to improve the GI tolerability of mycophenolic acid (MPA). EC-MPS 720 mg b.i.d. has earlier been shown to be therapeutically equivalent to mycophenolate mofetil (MMF) 1000 mg b.i.d. in de novo kidney recipients (M. Salvadori et al. Am J Transplant 2004;4:231–236).

Durable Engraftment and Long-Term Survival Following Fludarabine-Based Nonmyeloablative Hematopoietic Cell Transplantation (HCT) in Patients with ATG-Refractory Severe Aplastic Anemia (SAA) and Other Nonmalignant Hematological Disorders.

We evaluated the toxicity-profile, engraftment potential, and efficacy of fludarabine-based nonmyeloablative allogeneic HCT in patients with a variety of nonmalignant hematological disorders. Twenty three patients (median age 29 years; range 11–52) with nonmalignant hematological disorders including ATG refractory SAA (n=13), severe paroxysmal nocturnal hemoglobinuria (PNH: n=9), and pure red cell aplasia (PRCA; n=1) were transplanted from 5/99 – 8/2004 at the NHLBI. The majority of patients had an extensive transfusion history including 11/23 who had HLA allo-antibodies and 4/23 with allo-antibodies to RBCs. Conditioning with fludarabine (25 mg/m2 x 5 days), ATG (40mg/kg x 4 days) and cyclophosphamide (60mg/kg x 2 days) was followed by infusion of an un-manipulated G-CSF mobilized allograft from an HLA matched sibling (n=18), parent (n=2), or single antigen mismatched sibling (n=3). GVHD prophylaxis consisted of cyclosporine (CSA) either alone (n=2) or combined with mycophenolate mofetil (n=10) or mini-dose methotrexate (n=11). Despite a high prevalence of pre-transplant allo-immunization, all patients achieved sustained donor engraftment in both myeloid and T-cell lineages. Myeloid recovery (neutrophils >500cells/uL) occurred at a median 14 days post transplant (range 8–18 days). Conversion from mixed to full donor myeloid and T-cell chimerism occurred in all patients by 110 days post-transplant. CMV reactivation occurred in 11/21 patients at risk (KM probability 52%) without any cases of CMV disease. Grade II–IV and III–IV acute GVHD was the major transplant complication occurring in 13/23 (KM probability 60%) and 8/23 (KM probability 38%) patients respectively. Fourteen of 21 evaluable patients developed chronic GVHD (limited in 11 cases), which resolved completely with low-dose alternate day steroids and/or CSA in all but 1 case. One patient who received an allograft from his HLA matched father died 16 months post-transplant from complications related to chronic GVHD. With a median follow up of 25 months (range 1–64 months), 20/21 patients evaluable more than 100 days post-transplant survive in complete remission with full donor chimerism in all lymphohematopoietic lineages (KM probability of long-term survival 92.8 %-see figure ).Conclusion: Fludarabine-based nonmyeloablative transplantation achieves excellent donor engraftment and long-term disease free survival in heavily transfused and allo-immunized patients with ATG refractory SAA and other nonmalignant hematological disorders associated with bone marrow failure. [Display omitted]

Inhibition of Graft Coronary Arteriosclerosis after Heart Transplantation

Graft coronary arteriosclerosis (GCA) is the leading cause of long-term mortality after heart transplantation (HTx). The goal of this study was to demonstrate that inhibition of immunemediated injury by cyclosporine (CsA) protects the allograft from GCA. ACI-to-Lewis rat allografts were disparate in major and nonmajor histocompatibility loci. Isografts (Lewis-Lewis) were controls. Treatment groups received either olive oil or CsA at 2.5, 5, 10, or 20 mg/kg/day for 3 months. Histology (elastin) and immunohistochemistry using monoclonal antibodies to CD4, CD8, CD45R, RT1B, CD11b/c, CD25, and alpha-actin was performed to examine the epicardial and intramyocardial coronary arteries. Computerized image morphometry was utilized to measure intimal and medial thickness and area. Rats receiving olive oil or CsA at 2.5 mg/kg/day had severe rejection and no graft survival. CsA at 5 mg/kg/day resulted in less severe rejection with significant intimal and medial proliferation (P < 0.001). CsA at 10-20 mg/kg/day paralleled Lewis-Lewis isograft outcomes and inhibited arteriosclerotic vascular changes in the allograft (P < 0.001). Perivascular T-helper cells and macrophages were a characteristic finding with low-dose CsA but rare with higher CsA doses. In this new model of accelerated GCA in rats, immune-mediated antigen-dependent vasculopathy as a result of inadequate immunosuppresion is fundamental in the development of GCA, which appeared equally in epicardial arteries and intramyocardial arterioles. CsA prevents GCA in a dose-dependent fashion in the rat allograft.

Is sirolimus a safe alternative to reduce or eliminate calcineurin inhibitors in chronic allograft nephropathy in kidney transplantation?

Purpose We evaluate whether cyclosporine (CsA) or tacrolimus (FK) could be reduced or eliminated after sirolimus was added in chronic allograft nephropathy (CAN). By reducing doses of CsA or FK, we expected that renal function would improve. Method and material Twenty-one patients with CAN had sirolimus added as an immunosuppressive agent. We evaluated the creatinine (Cr) level 3 months after addition. The doses of CsA and FK were decreased gradually and then eliminated over a course of 4 to 6 weeks. If the Cr level rose rapidly or other prominent signs of rejection occurred; low-dose CsA or FK would be added per protocol. We evaluated the duration of engraftment before sirolimus and the Cr level when it was added. Results Renal function improved in 13 of 21 cases. The improvement in Cr ranged from 12.5% maximally to 1.84% minimally. Seven of 13 cases still required low-dose CsA. The average duration of engraftment before sirolimus was 13.66 ± 10.80 months. The average Cr level before sirolimus was 1.65 ± 0.56 mg/dL. In the other eight cases, the Cr level kept rising from 5.1% to 20.4%. The average duration of engraftment was 88.38 ± 42.21 months. The average Cr level before sirolimus was 2.85 ± 0.54 mg/dL. Hyperuricemia was noted in 31.3% and hyperlipidemia in 68.8%. Conclusion Sirolimus is a safe alternative to reduce or eliminate CsA or FK in CAN. In cases with a long duration of engraftment and high Cr level, sirolimus might have some effect as a substitute for CNI and thus prevent further nephrotoxicity.

Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology.

The role and burden of cyclosporine (CsA) nephrotoxicity in long-term progressive kidney graft dysfunction is poorly documented. The authors evaluated 888 prospective protocol kidney biopsy specimens from 99 patients taken regularly until 10 years after transplantation for evidence of CsA nephrotoxicity. The most sensitive histologic marker of CsA nephrotoxicity was arteriolar hyalinosis, predicted by CsA dose and functional CsA nephrotoxicity. Striped fibrosis was associated with early initiation of CsA and the need for posttransplant dialysis (both P < 0.05). The 10-year cumulative Kaplan-Meier prevalence of arteriolar hyalinosis, striped fibrosis, and tubular microcalcification was 100%, 88.0%, and 79.2% of kidneys, respectively. Beyond 1 year, 53.9% had two or more lesions of CsA nephrotoxicity. Structural CsA nephrotoxicity occurred in two phases, with different clinical and histologic characteristics. The acute phase occurred with a median onset 6 months after transplantation, was usually reversible, and was associated with functional CsA nephrotoxicity (P < 0.05), high CsA levels (P < 0.05), and mild arteriolar hyalinosis (P < 0.001). The chronic phase of CsA nephrotoxicity persisted over several biopsies, occurred at a median onset of 3 years, and was associated with lower CsA doses and trough levels (both P < 0.05). It was largely irreversible and accompanied by severe arteriolar hyalinosis and progressive glomerulosclerosis (both P < 0.001). A threshold CsA dose of 5 mg/kg/day predicted worsening of arteriolar hyalinosis on sequential histology. Pathologic changes of CsA nephrotoxicity were virtually universal by 10 years and exacerbated chronic allograft nephropathy. CsA is unsuitable as a universal, long-term immunosuppressive agent for kidney transplantation. Strategies to ameliorate or avoid nephrotoxicity are thus urgently needed.

CALCINEURIN INHIBITOR WITHDRAWAL IN RENAL TRANSPLANT RECIPIENTS: IMPROVEMENT IN RENAL FUNCTION AND REDUCTION OF CARDIOVASCULAR RISK

P239 Aims: Immunosuppressive regimens with cyclosporine (CSA) reduced the occurrence of acute rejection episodes in renal transplants, with better graft survival. However, side effects such as nephrotoxicity, systemic hypertension and metabolic disorders have a negative impact on patient survival, increasing the cardiovascular mortality. Regimens with lower CSA doses has been proposed to reduce cardiovascular risk. The aim of the present study was to analyze the safety and efficacy of slow CSA withdrawal in renal transplant patients with chronic allograft nephropathy (CAN). Methods: renal transplant patients followed >12 months, with impaired renal function (serum creatinine >1.5mg%) and/or hyperlipidemia and hyperuricemia were included in the present protocol. Immunossupressive regimen included full dose of mofetil mycophenolate (MMF, 2 to 3 grams/day) and at least 5 mg/day of prednisone. CSA dose was reduced in a step by step basis (0.5mg/kg/day every month), with complete withdrawal after 6 months of study. Clinical and laboratory data were analyzed at each time point. Results: 63 renal transplant patients (56 male, 7 female), mean age 41 ± 9 years old, recipients from cadaveric (n=39) or living related (n=24), followed for 66 ± 30 months post transplant (12 to 122 months) were included in this study. Sixty one patients completed the CSA withdrawn and no acute rejection episodes were observed during the study period (mean follow up of 8 months after withdrawal). Two patients were drop out because of GI intolerance to MMF. A significant reduction in both serum creatinine (2.05 ± 0.7mg/dl CSA treatment vs. 1.69 ± 0.7 mg/dl CSA free p<0.05), and in systemic blood pressure (104 ± 8 mmHg CSA vs. 97.5 ± 7 mmHg CSA free, p<0.05) occurred with CSA withdrawal. Increase in glomerular filtration rate occurred after CSA withdrawal (Cockrofi Gault clearance 64.5 ± 10.1 ml/min with CSA vs. 74.4 ± 9.4 ml/min, CSA free, p<0.05). A improvement in metabolic profile was also observed after CSA withdrawal, with reduction in both total cholesterol levels (233 ± 52 mg/dl vs. 196 ± 57 mg/dl, p<0.05) and serum uric acid levels (8.2 ± 1.7 mg/dl vs. 7.5 ± 1.6 mg/dl, p<0.05). The number and dose of anti-hypertension drugs, allopurinol and statins was also observed after CSA withdrawal.. Conclusions: in renal transplant patients with CAN and metabolic disorders, CSA withdrawal in presence of full dose MMF was safe, leading to a better blood pressure control and glomerular filtration recovery. The slowly reduction in CSA dosage avoided acute rejection episodes in this series. A longer follow up is needed in order to evaluate the effect of CSA free regimen in the occurrence of cardiovascular events.

CORTICOSTEROID AVOIDANCE AMELIORATES LYMPHOCELE FORMATION AND WOUND HEALING COMPLICATIONS ASSOCIATED WITH SIROLIMUS THERAPY: 2 YEAR FOLLOW-UP IN 109 PATIENTS

O10 Aims: Both sirolimus (RAPA) and corticosteroids (CS) have been shown to adversely impact wound healing. Moreover, since RAPA and CS may have additive effects on wound healing; we sought to determine if corticosteroid avoidance (CSAV) would ameliorate the wound healing complications associated with RAPA. Methods: 109 patients (pts) treated with a CSAV regimen (no pre or post transplant CS) were compared to a historical control group (n=72) that received cyclosporine (CsA), mycophenolate mofetil (MMF) and CS. The CSAV regimen included thymoglobulin (mean 2.6 doses), RAPA (8-12 ng/ml), MMF (2 grams/day), low-dose CsA, (trough 100 ng/ml, discontinued at 4-6 months. Complications were classified as: wound healing complications (WHC) or infectious wound complications (IWC). WHC include lymphocele, hernia, dehiscence, and skin edge separation. IWC include wound abscess and empiric antibiotic therapy for wound erythema. Results: The CSAV group was largely CS free: 11% of pts received CS for rejection, 12% received CS for recurrent disease and 85% of pts are currently off CS. 5% of patients who received CS developed wound complications however, CS were started after the development of all wound complications.FigureIn a subgroup analysis the reduction in lymphocele formation was seen primarily in patients with a BMI > 30 (3.5% vs. 31.8%, p=0.006). A multivariate analysis showed that African American race appears to be a strong risk factor for the development of any wound complication and wound healing complications. African Americans were 3.5 times more likely (CI 1.63-7.63, p=0.001) to develop any complication and 3.8 times more likely (CI 1.64-8.91, p=0.0002) to develop a wound healing complication. Those patients who received early CSWD were 18% less likely (CI 0.41-1.64, p=0.57) to develop any type of complication, 41% less likely (CI 0.26-1.33, p=0.20) to develop a wound healing complication, 71% less likely (CI 0.103-0.808, 0.018) to develop a lymphocele and 1.5 times more likely (CI 0.53-4.04, p=0.46) to develop and infectious complication. Conclusions: CSAV in a RAPA based regimen results in: 1) marked reduction in lymphoceles and WHC and 2) a reduction in lymphoceles primarily in obese patients. African American race appears to be a strong risk factor for the development of wound healing complications whereas CSWD offers protection against the development of lymphoceles and wound healing complications. CSAV provides a promising approach for addressing WHC associated with RAPA therapy. Transplantation, Volume 78, Number 2, July 27, 2004

INITIAL SELECTIN BLOCKADE OF T CELL ACTIVATION AND SIGNALLING COMBINED WITH LOW-DOSE SIROLIMUS AND CYCLOSPORINE IMMUNOSUPPRESSION PREVENTS CHRONIC REJECTION OF KIDNEY ALLOGRAFTS

P1141 Aims: We examined the efficacy of recombinant soluble P-selectin glycoprotein ligand (rPSGL-Ig) ± sirolimus (SRL) ± cyclosporine (CsA) in treating the accelerated chronic rejection (CR) of renal allografts from brain dead (BD) F344 donors transplanted into LEW recipients. Methods: rPSGL-Ig (50μg, iv) was administered to the donor 3 hrs after BD and immediately to the host after transplantation to inhibit initial cellular activity. As shown previously, this strategy inhibits T cell activation and signalling. SRL ± CsA was given to immunosuppress subsequent antigen-dependent responses. Grafts from all recipient groups (n=8-12/Gp) were examined histologically at 150 days. Activated CD4+CD25+ T lymphocytes and T cell signalling (signal 1 and 2: TCR/MHC class II and CTLA-4/B7-1/B7/2/CD28) were assessed using double immunostaining. Gene expression of IL-2, IL-10, IFN-γ, TNF-α, TGF-β, and ICAM-1 were measured with RNAse protection assay and Real Time PCR. Recipient groups included: Gp1 = isografts; Gp 2 = BD donor allografts in rats treated with CsA 1mg daily, 10days; Gp 3 = SRL 0.4mg daily 21; Gp4 = SRL (as above) + rPSGLIg (as above); Gp5 = SRL + CsA; Gp6 = SRL + CsA + rPSGL-Ig; Gp7 = SRL 0.1mg, 4-13 days + CsA + rPSGL-Ig. Results: At 150 days after transplantation, Gp1 grafts showed only minor (1/4+) signs of CR (tubular atrophy, interstitial fibrosis, and vascular obliteration). CR of Gp 2 allografts was moderate (2/4+) and extensive in Gp 3 allografts (3/4+). The addition of rPSGL-Ig protected the allografts of Gp 4 hosts substantially (1/4+). Severe tubular injury (4/4+) occurred with high dose SRL+CsA treatment (Gp 5), regardless of rPSGL-Ig (Gp 6). However, grafts of Gp 7 (low dose SRL + CsA + rPSGL-Ig) resembled isografts with inhibited gene expression (IL-2, IFN-γ, and TGF-β), sporadic CD4+CD25+ cells, and signal 1 and 2. Conclusions: Organs from recipients treated with high dose SRL ± CsA showed severe chronic changes, regardless of the effects of rPSGL-Ig on initial T cell activity. In contrast, selectin blockade acts synergistically with low dose SRL plus CsA to prevent CR of renal allografts from BD donors over the long-term.

Beneficial effect of concomitant induction with antilymphoblast globulin, cyclosporine, and steroids on long-term renal allograft outcome

Background The addition of induction therapy with antilymphocytic antibodies to cyclosporine (CsA) based immunosuppression, has reduced acute rejection incidence and improved short-term survivals, but has not had well-established effects on long-term renal transplant survival. Patients We analyzed the long-term allograft outcome of patients included in a prospective randomized clinical study conducted in our center 15 years ago by comparing two strategies: (A) horse antilymphoblast globulin (ALG) given at 10 mg/kg on alternate days to a maximum of 6 doses with low-dose CsA started at 8 mg/kg per day and prednisone at 0.25 mg/kg per day, versus (B) CsA started at 15 mg/kg per day and prednisone at 0.5 mg/kg per day. Diabetic and highly sensitized patients (PRA > 70%) were excluded from the study. Results The characteristics of the 50 patients enrolled in each group were not different. Although patient survival was not different (88% in group A vs 77% in group B), recipients treated with ALG showed a lower incidence of acute rejection episodes (20% vs 44%, P = .01) and better death-censored renal allograft survival (57% vs 41%, P = .03). Among rejection-free patients, graft survival was 15% higher in group A (60% vs 45%, P = .12). Multivariate Cox regression analysis showed that an acute rejection episode (relative risk [RR]: 2.44, 95% confidence interval [CI] 1.36–4.39; P = .0029) rather than ALG immunosuppression (RR 0.74, 95% CI 0.41–1.33; P = NS) was an independent predictor of death-censored graft survival. Conclusions In summary, we confirmed that concomitant induction therapy with ALG, CsA, and steroids improves long-term renal allograft survival.

Nephrotoxic aspects of cyclosporine

Over the last 20 years cyclosporine (CsA) has improved the survival of kidney, heart, and liver transplants. However, with increasing use, evidence has accumulated that CsA therapy carries a variety of side effects, the most important being renal toxicity. CsA can lead to a wide spectrum of renal function impairments, including a marked and rapidly reversible decrease in renal hemodynamics (acute CsA nephrotoxicity), and a chronic form of renal damage that potentially progress irreversibly to end-stage renal disease (chronic CsA nephrotoxicity). All these manifestations are the consequence of the drug toxic effects on renal vessels and the tubulointerstitium. A proper diagnosis of CsA toxicity at early stages, the combination of low CsA doses with non-nephrotoxic immunosuppressants, and the development of more feasible strategies to monitor daily CsA exposure may contribute to a better CsA management, improve quality of life of transplant recipients, and prolong graft survival.

Cyclosporine treatment for autoimmune sensorineural hearing loss

Rationale Autoimmune sensorineural hearing loss (ASNHL) remains without an adequate therapy other than corticosteroids. Here we report 2 patients who had a favorable response to cyclosporine (CSA). Cases/results Patient 1. A 58-year-old white male was diagnosed with ASNHL following an upper respiratory tract infection. He responded well to high dose prednisone but attempts at tapering were unsuccessful. CSA was started at 4 mg/kg/day with a dramatic response, which allowed tapering the prednisone to 20 mg/day. When CSA was tapered down, he had a prompt and significant worsening of his hearing and his word recognition dropped to 44%. Resuming the original dose of CSA brought his hearing back to baseline and his word recognition to 92% within a week. Patient 2. A 57-year-old white female underwent a left cochlear implant for longstanding hearing loss. One month following surgery, however, the hearing in both ears started to deteriorate. ASNHL was diagnosed. Despite continued high dose prednisone, the hearing in her right ear continued to deteriorate. CSA was started at 4 mg/kg/day. Her hearing improved markedly with word recognition improving to 86% with the hearing aid. 8 weeks later CSA was stopped because of incapacitating tremors. Her hearing then worsened significantly despite treatment with steroids. Conclusions ASNHL is a well-established autoimmune disease with poor response to most immunosuppressants. CSA has been successfully used in rheumatoid arthritis and, at low doses, in autoimmune urticaria. These two patients suggest that low dose CSA can be an invaluable tool in the treatment of ASNHL and, perhaps, other autoimmune disorders.

From cyclosporine to the future

Most of the experience acquired in our unit with cyclosporine (CsA) comes from randomized trials. A first trial demonstrated that CsA-treated patients had a better 10-year graft survival than azathioprine-treated patients. A second trial showed equivalence between double therapy with CsA plus steroids and triple therapy with CsA, steroids, and azatioprine. A third trial showed similar 2-year graft survival with CsA monotherapy and triple therapy. A larger multicenter study that compared three different CsA-based regimens showed similar long-term graft survival with monotherapy, double therapy, and triple therapy. However, patients given monotherapy had less frequent steroid-related side-effects. Finally a more recent multicenter international trial showed that the rate of acute rejection can be reduced without increasing side effects by adding the monoclonal antibody basiliximab to the triple therapy. By reviewing our cumulative experience with CsA we found a mean graft half-life of 18.7 years for cadaver renal transplant recipients and 31.9 for the living transplant recipients. No significant attrition of graft function was found for patients with grafts functioning at 15 years. Two important issues with the present immunosuppression concern the long-term nephrotoxicity of calcineurin inhibitors and the cardiovascular disease, which is at least in part related to the use of steroids. To face these problems, we are currently involved in two multicenter trials, one comparing sirolimus plus mycophenolate mofetil to sirolimus plus low-dose CsA, while the other trial compares certican plus CsA to certican plus CsA plus corticosteroids.

Experience with cyclosporine in endogenous uveitis posterior

Treatment with cyclosporine (CsA) has considerably improved the visual prognosis of patients suffering from endogenous posterior uveitis (EPU). However, the therapeutic benefits of CsA are partially outweighed by its many side effects, most notably nephrotoxicity and hypertension. Low-dose CsA regimens have reduced toxicity but have not been able to completely eliminate this problem. New therapeutic approaches, such as anti-tumor necrosis factor α treatment or immunosuppression with drugs including tacrolimus, sirolimus, and interleukin-2 receptor antibodies, are currently under evaluation. Hopefully such strategies will further reduce the morbidity of EPU and minimize the adverse effects associated with conventional therapies.

The role of the protocol biopsies in renal allograft recipients

Subclinical rejection and long-term cyclosporine nephrotoxicity are well-known risk factors of chronic allograft nephropathy. In a prospective study 32 low-risk patients were randomized to either a reduced CsA dose (5 mg/kg/d) and daclizumab (group A, n = 16) for 7 months posttransplant with subsequent CsA tapering/withdrawal, or to a normal CsA dose (10 mg/kg/day) without daclizumab (group B, n = 16). Both groups received MMF and prednisone. Protocol biopsies were obtained at engraftment and 3 and 12 months after Tx. The number of rejection episodes was the primary endpoint. The secondary endpoints were: renal function, histological parameters related to CsA, and serum levels of TGF-β and PDGF-BB. A low incidence of clinically suspected rejection episodes was observed (19% in group A and 12.4% in group B; P = NS). Although protocol biopsies showed 12 subclinical rejection episodes (six in group A, six in group B), serum creatinine levels were not different between the examined groups at 3 months. However, at 12 months, there was a statistically improved mean creatinine level in group A patients (1.2 mg/dL ± 0.5 in group A vs 1.54 mg/dL in group B; P < .05). Chronic histopathologic changes were significant for biopsies at 3 and 12 months in both groups compared to the baseline findings for protocol biopsies (with no differences between groups, or between 3 and 12 months in both groups). Serum TGF-β and PDGF-BB did not differ between the groups. Protocol biopsies may be useful to monitor safety and efficiency of new immunosuppressive protocols. Immunosuppressive regimens with low CsA doses followed by the drug's complete withdrawal seem to be efficient and safe in low-risk kidney allograft recipients.

Sirolimus-based immunosuppression with reduce dose cyclosporine or tacrolimus after renal transplantation

Sirolimus (SRL), a fermentation product of Streptomyces hygroscopicus, complexes with the FKBP12 to inhibit cyclin dependent kinase(s), collectively termed the target of rapamycin (TOR), causing G 1–S phase cell cycle arrest. Safety and efficacy have been documented in clinical renal transplantation, but concerns were raised due to important biologically relevant side effects. Hyperlipidemia was identified, beginning with early clinical experiences, and the unexpected findings that SRL may exacerbate CsA associated nephrotoxicity was observed during the pivotal phase III studies. This report details results of our experience using SRL (target trough concentration, 10–15 ng/mL) with low dose CsA (target trough concentration, 50–100 ng/mL), seeking to determine whether this approach might provide effective immunosuppression while reducing associated nephrotoxicity. Among 121 renal transplant recipients, 62 received the SRL based regimen and 59 received MMF with all patients receiving CsA and prednisone. Similar to earlier clinical experiences, hematopoeitic abnormalities and hyperlipidemia were observed among patients who received SRL, and those abnormalities were readily controlled. However, unlike observations from the phase III SRL studies, renal function was not adversely affected. These findings support the growing body of evidence indicating that SRL based immunosuppression in combination low dose calcineurin inhibitors and corticosteroids is safe, efficacious, and without associated renal toxicity.

Prolongation of small bowel allograft survival with a sequential therapy consisting of a synthetic MHC class II peptide and temporarily low-dose cyclosporine A

It has been extensively documented the role of the indirect pathway of allorecognition in allograft rejection. However, recent data demonstrate that the manipulation of this pathway could be also sufficient to promote prolongation of allograft survival. In the present study we evaluated the effect of preoperative immunization with the WF-specific MHC class II peptides RT1.D2 and RT1.B2 in combination with low-dose CsA from days 0 to 7 (5 mg/kg/day) and from days 8 to 30 (1 mg/kg/day) after WF small bowel transplantation. Seven days before and on the day of transplantation, LEW recipients were immunized with the two WF MHC class II peptides RT1.B2 and RT1.D2. The CsA monotherapy induced an allograft survival of 49.3 ± 6.1 days. MHC class II peptide immunization had a limited effect on allograft survival for RT1.D2 (47.1 ± 3.8 days) and induced prolongation of allograft survival for RT1.B2 (73.6 ± 34.6 days). This effect seems to be based on the absence or silence of RT1.B2-reactive T cells and rejection seems to be correlated with the presence of RT1.B2-specific T cells in the late phase. Therefore, the combination of RT1.B2 with low-dose CsA shifts the immunological response and protects small bowel allograft rejection.

Prevention of chronic rejection by pravastatin in a rat kidney transplant model.

Pravastatin when administered with cyclosporine (CsA) has been shown to ameliorate transplant vasculopathy in the clinical setting. Previously we showed that pravastatin prevents chronic rejection in rat cardiac and liver transplant models. Here we determine whether pravastatin prevents chronic rejection in a rat renal allograft model. Orthotopic renal transplantations were performed using Fisher 344 rats as donors and Lewis rats as recipients. Recipients were treated with low-dose CsA for 10 days to prevent acute rejection. Recipients were divided into three groups: CsA, CsA + pravastatin, and syngeneic. Renal function was assessed by serum creatinine level at day 130. Allografts were evaluated by histology and immunohistochemistry. Serum levels of alloantibodies were measured by flow cytometry. Intragraft cytokine mRNA expression was determined by semiquantitative reverse transcriptase-polymerase chain reaction. Intragraft levels of the antiapoptotic Bag-1 gene were measured by Western blot. Unlike allografts from the pravastatin group, control allografts demonstrated glomerulosclerosis, vascular obliteration, tubular atrophy, and interstitial fibrosis. Serum creatinine levels and graft infiltration of T cells and macrophages in the pravastatin-treated animals were significantly lower. Intragraft cytokines showed a T helper 2 polarization and decreased transforming growth factor-beta in the pravastatin group. Intragraft expression of Bag-1 was increased in the pravastatin group. This study demonstrates the ability of pravastatin to inhibit chronic rejection in rat renal allografts. Pravastatin's pleiotropic effects of reducing intragraft inflammatory cytokines, inhibiting immune cell infiltration, and causing up-regulation of the antiapoptotic gene Bag-1 suggest that its ability to prevent transplant chronic rejection may be multifactorial.